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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2719
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2084-2088
Copyright © 2008 by The Endocrine Society

Beneficial Effects of Propylthiouracil plus L-Thyroxine Treatment in a Patient with a Mutation in MCT8

J. L. Wémeau, M. Pigeyre, E. Proust-Lemoine, M. d'Herbomez, F. Gottrand, J. Jansen, T. J. Visser and M. Ladsous

Clinique Endocrinologique Marc Linquette (J.L.W., M.P., E.P.-L., M.L.), Laboratoire de Médecine Nucléaire (M.d’H.), and Unité de Gastro-entérologie et Nutrition Pédiatrique (F.G.), Centre Hospitalier Universitaire, 59 037 Lille, France; and Department of Internal Medicine (J. J., T.J.V.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: J. L. Wémeau, Clinique Endocrinologique, 6 rue du Pr Laguesse, CHRU, 59 037 Lille Cedex, France. E-mail: jl-wemeau{at}chru-lille.fr.


   Abstract
Top
 Abstract
Introduction
 Case Study
 Discussion
 References
 
Context: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct X-linked phenotype of severe psychomotor retardation and consistently elevated T3 levels. Lack of MCT8 transport of T3 in neurons could explain the neurological phenotype.

Objective: Our objective was to determine whether the high T3 levels could also contribute to some critical features observed in these patients.

Results: A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had tachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated serum free T3 (FT3) level (11.3 pmol/liter), without FT4 and TSH abnormalities. A missense mutation of the MCT8 gene was present. Oral overfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) and then PTU plus levothyroxine (LT4) was tested. After PTU (200 mg/d), serum FT4 was undetectable, FT3 was reduced (3.1 pmol/liter) with high TSH levels (50.1 mU/liter). Serum SHBG levels were reduced (72 nmol/liter). While PTU prescription was continued, high LT4 doses (100 µg/d) were needed to normalize serum TSH levels (3.18 mU/liter). At that time, serum FT4 was normal (16.4 pmol/liter), and FT3 was slightly high (6.6 pmol/liter). Tachycardia was abated (84 beats/min), weight gain was 3 kg in 1 yr, and SHBG was 102 nmol/liter.

Conclusions: 1) When thyroid hormone production was reduced by PTU, high doses of LT4 (3.7 µg/kg·d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T3 levels might exhibit some deleterious effects on adipose, hepatic, and cardiac levels. 3) PTU plus LT4 could be an effective therapy to reduce general adverse features, unfortunately without benefit on the psychomotor retardation.


   Introduction
Top
 Abstract
 Introduction
Case Study
 Discussion
 References
 
Monocarboxylate transporter 8 (MCT8), encoded by a gene located on human chromosome Xq13.2 is an active transporter facilitating cellular entry of thyroid hormone (TH) (1). MCT8 is expressed in numerous human tissues, especially brain, heart, placenta, lung, kidney, skeletal muscle, and liver. Mutations of the MCT8 gene result in a distinct X-linked phenotype of severe psychomotor retardation and strongly elevated T3 levels (2, 3). Lack of MCT8 transport of T3 in neurons could explain the neurological phenotype (4). Currently, no therapy is available to improve the condition of the patients.

The aims of our study were to determine whether the high T3 levels could also contribute to some critical features observed in patients with MCT8 mutations, also known as the Allan-Herndon-Dudley syndrome (AHDS) (5), and whether treatment aimed at reducing circulating T3 levels could be of benefit to these patients.


   Case Study
Top
 Abstract
 Introduction
 Case Study
Discussion
 References
 
A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (weight 25 kg, height 142 cm, body mass index 12.4 kg/m2) and delayed puberty (Tanner stage 1). Since birth, mental development was severely disturbed; he had no hearing loss but was unable to speak and showed few reactions to external stimuli and little communication with the parents and the medical personnel. Moreover, he exhibited severe hypotonia, with no possibility of standing, of sitting without being belted, or of keeping his head upright. A divergent strabismus was present and a cleft palate. Permanent tachycardia (104 beats/min) was observed. Testicular glands were of low volume (4 ml); penis was prepubertal. Pubic hair was according to Tanner stage P1.

In contrast with the low T3 syndrome expected in an undernourished patient, serum free T3 (FT3) level was elevated (11.3 pmol/liter; normal, 3.3–6.2 pmol/liter), without FT4 (14.5 pmol/liter) or TSH (1.54 mU/liter) abnormality. The clinical phenotype and isolated high FT3 levels were suspicious for an MCT8 mutation, which was thus investigated. A missense mutation 812G->A (Arg271His) was detected in exon 3 of the MCT8 gene. Both his mother and one of his three sisters were found to be carriers of this mutation.

Table 1Go summarizes the initial biological data of the patient. Serum cholesterol and retinol binding protein were decreased, whereas the SHBG level was high (261 nmol/liter; normal, 15–45 nmol/liter). Testosterone level was low without an increase of serum gonadotropins.


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  		TABLE 1. Initial biological features

 
Malnutrition was one of the reasons that the patient was referred to our medical clinic. Oral overfeeding (1600 kcal/d) was unsuccessful (gain of weight 200 g/yr). Gastrostomy was advised by the nutritionists of our hospital. However, considering the putative effect of high T3 serum levels on the adipose and muscular tissues, we tested the therapeutic effect of propylthiouracil (PTU), first alone and subsequently in combination with levothyroxine (LT4) replacement. Written informed consent of both parents was obtained. After 12 and 24 wk of PTU treatment (200 mg/d), serum FT4 was undetectable (<2.9 pmol/liter), FT3 was reduced (2.7, 3.1 pmol/liter), and TSH levels were high (25.3–50.1 mU/liter). Thyroglobulin (Tg) levels were increased (from 11.4 to 874 ng/ml). An increase in thyroid volume was concomitantly measured by ultrasonography (from 5 to 25 ml). Serum SHBG levels were reduced (46.8 and 72 nmol/liter). While PTU prescription was continued, high LT4 doses (100 µg/d) were needed to normalize serum TSH levels (3.18 mU/liter). At this time, serum FT4 was normal (16.4 pmol/liter), and FT3 was slightly high (6.6 pmol/liter). Tachycardia abated (84 beats/min), gain of weight was 3 kg in 1 yr, and SHBG was 102 nmol/liter (Fig. 1Go).


Figure 1
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  		FIG. 1. Evolution of serum FT3, FT4, TSH, and Tg, of thyroid volume, body mass index (BMI), heart rate, and SHBG concentrations after therapy with 200 mg/d PTU and then PTU plus LT4 at 50, 75, and 100 µg/d. PTU alone reduced FT4, normalized FT3, and increased TSH, Tg levels, and thyroid volume. When high doses of LT4 were added, in comparison with initial values, TSH and FT4 levels were similar, whereas a weighty reduction of FT3 concentration was obtained. Therapy improved body mass index and reduced heart rate and SHBG levels.

 
Resting energy expenditure (REE) was measured by indirect calorimetry at diagnosis and then after PTU and on PTU plus LT4 treatment. Inspired oxygen flow (VO2), expired carbon dioxide flow (VCO2), and the respiration quotient (RQ) were noted. REE was calculated every minute from oxygen consumption (VO2 in milliliters per minute), as was production of carbon dioxide (VCO2 in milliliters per minute). Continuous respiratory exchange measurements were conducted for a minimum period of 30 min. Coefficients of variation were less than 10% for VO2 and dilution airflow and less than 5% for RQ (6). Predicted REE was calculated using the Schofield equation (7) and compared with the REE measured by indirect calorimetry. REE increased from 881 kcal (predicted 931 kcal) at baseline to 1160 kcal (predicted 1164 kcal) 3 months after PTU treatment and 1207 kcal (predicted 1158 kcal) on PTU plus LT4. RQ remained stable (0.82, 0.81, and 0.80, respectively) during treatment.


   Discussion
Top
 Abstract
 Introduction
 Case Study
 Discussion
References
 
The AHDS was described in 1944 as inherited sex-linked idiocy and microcephaly (8). Only male subjects were affected, suggesting an X-linked disease. Patients exhibit hypotonia with feeding difficulties and inability to sit or stand up and walk in most of the cases. Development of rigidity and contractures of the limbs are usual. Some choreoathetosis movements or paroxysmal dyskinesias can be observed. Cognitive functions are severely affected (5, 8, 9, 10). In 2004, mutations of MCT8 gene were identified by two groups in seven families in which males exhibited severe psychomotor retardation and hypotonia coexisting with high serum T3 levels (2, 3). One year later, a mutation of MCT8 was identified in the family originally described in 1944 and in other families previously reported with AHDS (5, 11).

Because MCT8 is importantly involved in the neuronal transport of T3 (1), lack of T3 supply to these cells during brain development probably explains the severe mental deficiency and the low psychomotor development of the patients. One could expect that high T3 level is related to reduction of metabolic clearance of T3, because its intracellular entrance is reduced and thus its access to neuronal type 3 deiodinase (D3). However, in male MCT8 knockout mice, after injection of 125I-labeled iodothyronines, T3 disappears from serum quite at the same rate as in wild-type mice (12), and T3 generation by D1 and D2 is increased, which has also a consumptive effect on T4 levels (13). These mice also show a reduced T3 feedback at the hypothalamic and/or pituitary level (12). Furthermore, T4 is required to maintain the high T3 level (13).

The patient who was referred to us exhibited all the clinical and biological features of AHDS and, not surprisingly, had a familial transmitted MCT8 mutation.

The patient had a permanent tachycardia (100–120 beats/min). He had no evidence of cardiac insufficiency, and cardiac acoustic and echocardiographic examinations were normal. Moreover, despite correct nursing, malnutrition was a preoccupant immediate problem of the patient. Therefore, we suspected deleterious effects of high T3 levels at the cardiac level and on adipose and muscular tissues.

In a first step, reduction of TH levels was obtained by an antithyroid drug. PTU was chosen preferentially to methimazole in view of the additional inhibition of D1 by PTU. PTU was given in a dose of 200 mg/d to the patient weighing 25 kg. No side effect was observed. Both T4 and T3 concentrations were reduced. TSH level increased, resulting in the development of a goiter with high serum Tg concentrations. Although the PTU regimen was not modified, the patient was additionally treated with progressive doses of LT4 to increase TH levels. High doses of LT4 (100 µg/d, corresponding to 3.7 µg/kg·d) were needed to normalize the TSH levels and to reduce the goiter and serum Tg. This is in keeping with a state of partial resistance to TH.

In parallel, the general status of the patient improved. The cardiac frequency abated to 84 beats/min. The weight gain was 3 kg/yr vs. 200 g/yr with the conventional oral overfeeding. For this reason, the nutritionists decided to renounce the gastrostomy initially planned for the patient. Treatment with PTU alone or with PTU plus LT4 did not significantly influence REE in our patient. The 32% increase in REE we observed 1 yr after PTU treatment can be explained by the improvement of nutritional status; indeed, measured REE remained closely correlated to predicted REE according to weight and height, whatever the treatment.

Unfortunately, the combined treatment with PTU and LT4 had no effect on the cerebral disturbances of the disease and the psychomotor retardation of the young patient.

Definitely, the MCT8 deficiency syndrome constitutes a novel etiology of resistance to TH. In this situation, conventional doses of TH fail to produce the usual effect. This was obvious, because when the endogenous production was totally reduced by PTU, high doses of LT4, twice higher than usual, were needed to restore normal TSH concentrations. This suggests that not only cellular T3 entry but also that of T4 is reduced. This gives an explanation of one of the most surprising features of the disease: TSH concentrations are normal or even increased despite high T3 levels (3).

Interestingly, in AHDS, the effect of a high T3 level seems to be expressed at the cardiac, muscular, adipose, and hepatic levels, as suggested by tachycardia, weight loss, and high SHBG concentrations. Some patients with resistance to TH due to TH receptor-β mutations exhibit tachycardia or cardiac disorders (14) and hyperkinetic behavior and hyperactivity (15), related to the influence of high TH concentrations on tissues with a normal TH receptor-{alpha} function. In patients with MCT8 mutations, tissues in which MCT8 does not play an important role in T3 uptake are exposed to high T3 levels and may be in a thyrotoxic state. Low cholesterol and very high SHBG levels were also observed in a 4-yr-old boy, carrying an MCT8 mutation described by Biebermann et al. (16), in whom only high doses of LT4 (100 µg) plus LT3 (30 µg/d) were able to reduce significantly TSH and increase SHBG levels with no change of the mental and psychomotor development.

Conclusions

1) In our patient with all the phenotypic and genetic characteristics of AHDS, when TH production was reduced by PTU, high doses of LT4 (3.7 µg/kg·d) were needed to normalize serum TSH. Definitely, this gives clinical evidence that mutation of MCT8 is a cause of resistance to TH, affecting not only T3 but also T4 cellular entrance. 2) In contrast, high T3 levels might exhibit some deleterious effects at the adipose, hepatic, and cardiac levels. As the two faces of Janus, lack of intraneuronal T3 explains severe psychomotor deficiency, while at the same time, an excess of circulating T3 could explain some peripheral features of the patients. 3) PTU plus LT4 treatment could be an effective therapy to improve the general condition of these patients, unfortunately without benefit on the psychomotor retardation.


   Acknowledgments
 
We gratefully thank E. Friesema and S. Manouvrier-Hanu for contributions to genetic counseling and L. Beghin for measures of resting energy expenditure.


   Footnotes
 
Disclosure Information: J.L.W., M.P., E.P.-L., M.d’H., F.G., J.J., T.J.V., and M.L. have nothing to declare. There are no conflicts of interest.

First Published Online March 11, 2008

Abbreviations: AHDS, Allan-Herndon-Dudley syndrome; D3, type 3 deiodinase; FT3, free T3; LT4, levothyroxine; MCT8, monocarboxylate transporter 8; PTU, propylthiouracil; REE, resting energy expenditure; RQ, respiratory quotient; Tg, thyroglobulin; TH, thyroid hormone.

Received December 10, 2007.

Accepted March 3, 2008.


   References
Top
 Abstract
 Introduction
 Case Study
 Discussion
 References
 

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